tbuckley/cabot-search huggingface dataset:
Factors associated with response to neoadjuvant chemotherapy and immune checkpoint inhibition in triple-negative breast cancer.
Authors: Alexis LeVee, Megan Wong, Sarah Flores, Nora H. Ruel, Sayeh Moazami Lavasani, Niki Patel, Mina S. Sedrak, Daphne B. Stewart, James Ross Waisman, Yuan Yuan, Joanne E. Mortimer
Journal: Journal of Clinical Oncology (2023)

e12593 Background: Immune checkpoint inhibition with pembrolizumab plus neoadjuvant chemotherapy is now the standard-of-care in patients with high-risk triple-negative breast cancer (TNBC) based on the KEYNOTE-522 trial. The trial demonstrated that the addition of pembrolizumab improves pCR, but it is currently unclear which patients benefit most from the addition of immunotherapy (IO). We sought to identify which demographic and clinical characteristics were associated with response to neoadjuvant pembrolizumab plus chemotherapy. Methods: We performed a single institution, retrospective study of early-stage TNBC patients treated with neoadjuvant chemotherapy and pembrolizumab between March 1 st , 2020 and December 1 st , 2022. We excluded patients who had not undergone definitive surgery. We collected demographic information, clinical and pathologic characteristics, and treatment data. Pathologic complete response (pCR) was defined by ypT0/Tis and ypN0. Multivariate analysis was performed using logistic regression to identify factors associated with pCR. This study was approved by the City of Hope Institutional Review Board. Results: 67 patients were analyzed with a median age of 56 years and median BMI of 29. Self-reported racial groups included 25 Hispanic patients (37%), 23 non-Hispanic White (34%), 9 Asian (13%), 6 Black (9%), and 4 other/unknown (6%). 6 (9%) patients were BRCA1+ and 1 (1.5%) patient was BRCA2+. The majority of patients had invasive ductal carcinomas (91%), were clinical T2 stage (65.7%), and node negative (52.2%). The median number of cycles of neoadjuvant IO was 7 (IQR 4-8) and median months from start of IO to surgery was 6 (IQR 4.6-6.7). 42 (62.7%) patients had a pCR. Multivariate results showed that patients under 50 years at time of diagnosis (vs. age &gt; 50 years), those with grade 3 (vs. 2), and those receiving 7 or more cycles of pembrolizumab (vs. &lt; 7) had improved rates of pCR (ORs 5.7, 8.1, and 3.4, respectively, p &lt; 0.05). BMI, race, BRCA1/2 status, histopathology, clinical T and N stage, and timing of start and end of IO to surgery were not significantly associated with pCR. Conclusions: Younger TNBC patients with high tumor grade were more likely to respond to treatment with neoadjuvant pembrolizumab and chemotherapy. More cycles of treatment with pembrolizumab was also associated with response. Further research to identify which patients with TNBC benefit from the addition of pembrolizumab to chemotherapy is necessary to determine whether its additional toxicity and cost are warranted.
Multicenter study to evaluate the efficacy and standardize radiofrequency ablation therapy for early breast cancer.
Authors: Takayuki Kinoshita, Shin Takayama, Masato Takahashi, Tomomi Fujisawa, Manabu Futamura, Naohito Yamamoto, Tadahiko Shien, Kenjiro Aogi, Tatsuya Ohnishi
Journal: Journal of Clinical Oncology (2023)

e12570 Background: Early-stage breast cancer is increasingly detected by screening mammography, and we aim to establish radiofrequency ablation therapy (RFA) as a minimally invasive, cost-efficient, and cosmetically acceptable local treatment. In our Phase I study, localized tumors with a maximum diameter of 2 cm, preoperatively diagnosed by imaging and histopathology, were treated with RFA. A 90% complete ablation rate was confirmed histopathologically. Our phase II multicenter study of RFA without resection for early breast cancer will evaluate the long-term safety and efficacy of RFA as well as its cosmetic results, which are a perceived advantage of this technique. Methods: From Nov. 2009 to Nov. 2012, 58 patients with early-stage breast cancer received non-surgical RFA therapy. Patients had localized solitary N0 tumors with a maximum diameter of 1 cm. In our experimental therapy, a radiofrequency electrode needle is inserted through the skin into the breast lesion under imaging guidance, followed by thermal ablation with radiofrequency waves. RFA will be conducted under general anesthesia. The Cool-tip™ RF Ablation Single Electrode Kit (Medtronic, CO, USA) will be used to standardize the evaluation of the ablation effect. They underwent RFA and SNB under general anesthesia and adjuvant therapy and breast radiation. Follow-up evaluation for residual tumor at 3, 6, and 12 months after RFA included clinical examination, diagnostic imagings and vacuum-assisted biopsy. Surgical resection was recommended for patients with suspected residual disease or incomplete ablation. The primary endpoint was the frequency of adverse events. Secondary endpoints included the complete ablation rate and ipsilateral breast relapse-free rate. Results: The follow-up period ranged from 15 to 109 months (median, 85 months). The 57 patients completed the non-surgical RFA procedure and underwent diagnostic imaging and needle biopsy after 3 months. Seven patients with suspected incomplete ablation underwent surgical resection; incomplete ablation was confirmed in 5 (8.6%, 2 with invasive and 3 with non-invasive ductal carcinoma). During subsequent follow-up, 1 patient each was diagnosed with contralateral breast cancer and ipsilateral breast tumor relapse. No distant recurrence was documented. Cosmetic results were excellent in 94% of patients. Conclusions: Our phase II multicenter study of RFA without resection for early breast cancer will evaluate the long-term safety and efficacy of RFA as well as its cosmetic results, which are a perceived advantage of this technique. Clinical trial information: UMIN000008675 .
Incidental discovery of second primary malignancies in patients diagnosed with breast cancer: An institutional case series.
Authors: Alexandra Iancu, Poorni Manohar, Shaveta Vinayak, William R. Gwin, Hannah M. Linden, Jennifer M. Specht, Lynn Katherine Symonds, Nancy E. Davidson, Natasha Hunter
Journal: Journal of Clinical Oncology (2023)

e12552 Background: National guidelines recommend tissue biopsy of suspected recurrent breast cancer, to confirm diagnosis and to characterize disease phenotype, receptor status, and molecular markers. Despite this, clinicians frequently rely on imaging alone to diagnose recurrent breast cancer; indeed, our group recently published data revealing that only half of patients in Washington state diagnosed with metastatic breast cancer between 2008 and 2017 underwent confirmatory biopsies for suspected metastatic disease on imaging. Here we present evidence of how this failure to fully evaluate suspected breast cancer recurrence could potentially lead to misdiagnosis. Methods: We surveyed our breast medical oncology faculty to identify patients treated at Fred Hutchinson Cancer Center (FHCC) from 2018 to 2022 in which a second primary carcinoma (not including non-melanoma skin cancers) was discovered as part of breast cancer workup and treatment. Results: We identified 10 cases of second primary diagnoses. Of these, the majority (7/10) were lung cancer; other diagnoses included neuroendocrine tumors (1), chronic lymphocytic leukemia (1), and thyroid cancer (1). In the case of lung cancers, patients were typically diagnosed during staging or CT evaluation for radiation or reconstruction, in which a pulmonary nodule raised suspicion for malignancy. In five cases, patients were treated with curative intent for both of their early-stage primary malignancies, and remain disease-free on endocrine therapy alone. In two cases, patients with biopsy-proven metastatic breast cancer were found to have new suspicious lung lesions, which on biopsy were found to represent lung adenocarcinoma; these patients were treated surgically for their lung cancer and continued long-term therapy for metastatic breast cancer. Conclusions: While imaging can raise strong suspicion for metastatic recurrence of breast cancer, the assumption that an apparently metastatic lesion 1) indeed represents metastasis and 2) represents metastatic spread of the known primary rather than another malignancy, risks treating both the primary tumor and the newly detected condition inappropriately. Biopsy is critical for confirmation of metastatic disease vs second primary or other etiology. As patients with metastatic breast cancer are surviving longer as our cancer-directed therapies improve, appropriate diagnostic measures for a suspicious non-breast malignancy are recommended for optimal care. Novel imaging modalities such as 18F-fluoroestradiol (FES) PET and others could be explored in discriminating between metastatic lesions and unrelated conditions.
ARID1A deficiency in triple-negative breast cancer induces adaptive immune resistance and sensitivity to immune checkpoint inhibitors.
Authors: Margaret Chen, Bin Li, Ye Wang, Xichun Hu, Zhonghua Tao
Journal: Journal of Clinical Oncology (2023)

1088 Background: Adaptive immune resistance (AIR) is pivotal to triple-negative breast cancer (TNBC) progression. Although immune checkpoint inhibitors (ICIs) shed new light on reversing AIR, the treatment effect and predictive markers of immunotherapy remain controversial. The present study focused on epigenetic regulation for TNBC AIR and explored whether this could be clinically targeted. Methods: Through screening an epigenetic gene set in TNBC patients from The Cancer Genome Atlas (TCGA), ARID1A was pinpointed as most significantly correlated with AIR. Humanized immune system (HIS) mice were adopted for TNBC transplantation, identifying CD8 + T cells as most significantly correlated with TNBC ARID1A. To probe the mechanism underlying TNBC ARID1A deficiency-induced CD8 + T cell malfunction and AIR, RNA-seq of both TNBC patients and TNBC cell lines were analyzed and the candidate mediator gene, PD-L1, was identified and verified through western blot, qPCR, IHC, dual luciferase reporter assay and cell co-culture. Chromatin immunoprecipitation and ATAC-seq further demonstrated direct binding of ARID1A to NPM1 promoter to regulate PD-L1 expression. Finally, HIS mice were treated with ICI and the clinical trial CTR20191353 was retrospectively analyzed. Results: Among a series of epigenetic modulators, we first observed that ARID1A, a core subunit of the chromatin remodeling complex SWI/SNF, demonstrated highest correlation with AIR in TNBC patients. This was verified in HIS TNBC mice and a patient cohort from Fudan University Shanghai Cancer Center by higher malignancy observed in ARID1A-deficient TNBC. Both bulk and single-cell RNA-seq in TNBC patients uncovered an immunosuppressive microenvironment induced by TNBC ARID1A deficiency, and CD8 + T cells was identified as the immune cell type most significantly correlated with TNBC ARID1A. CD8 + T cell malfunction and AIR in ARID1A-deficient TNBC was induced by upregulated PD-L1, but ARID1A did not directly regulate PD-L1 expression. We found that ARID1A bound to the NPM1 promoter and that ARID1A deficiency increased NPM1 chromatin accessibility as well as gene expression, further activating PD-L1 transcription. In HIS mice, ICI demonstrated the potential to reverse TNBC ARID1A deficiency-induced AIR manifested by reducing tumor malignancy and activating antitumor immunity. In CTR20191353, a phase 1b clinical trial of pucotenlimab combined with chemotherapy for TNBC, patients with ARID1A deficiency demonstrated significantly better prognosis and the longest progression-free survival was found in ARID1A-low/PD-L1-high group. Conclusions: In AIR epigenetics, TNBC ARID1A deficiency induced AIR via the ARID1A/NPM1/PD-L1 axis, leading to poor outcome. While ARID1A deficiency provided survival advantage for TNBC cells, it simultaneously left the Achilles' heel which could be targeted with ICI.
Clinical meaning of stromal tumor infiltrating lymphocytes (sTIL) in luminal early breast cancer.
Authors: Esmeralda García-Torralba, Alejandra Ivars-Rubio, Miguel Perez-Ramos, Esther Navarro Manzano, Noel Blaya-Boluda, Pilar de la Morena Barrio, Elisa Garcia-Garre, Gema Marin Zafra, Francisco Martinez-Diaz, Francisco Gomez Martinez, Javier Lopez-Robles, Beatriz Alvarez Abril, Elena Garcia Martinez, Francisco Ayala
Journal: Journal of Clinical Oncology (2023)

572 Background: Luminal breast cancer (BC) is associated with lower immune activation. Although stromal tumor infiltrating lymphocytes (sTIL) are a marker of better prognosis and response in hormone receptor (HR) negative tumors, sTIL predictive and prognostic implications are less clear in luminal BC. Further insights on the clinical correlations of immune microenvironment in luminal disease may facilitate therapeutic improvement and prognostic stratification in these patients. Methods: Observational and single-center cohort of 345 women with early luminal (HR positive, HER2 negative) BC (2012-2020) treated with chemotherapy. Pre-treatment sTIL were determined in the diagnostic biopsy following validated standard methods. The correlation between sTIL and other tumor characteristics were analyzed (Spearman's Rho and Chi-squared tests). Association of sTIL with pathologic complete response (pCR) in patients treated with neoadjuvant chemotherapy (nCT) was evaluated with logistic regression models. Prognostic value of sTIL for overall (OS) or relapse free interval (RFI) was analyzed by Cox regression models. Results: Median age: 50 (range: 24-89); 48.1% premenopausal; 91.3% infiltrating ductal carcinoma; 30.1% grade 3; 87.2% progesterone receptor (PgR)+; 67.5% treated with nCT and 32.8% with adjuvant CT (aCT); 47.6% N0, 32.8% N1, 19.6% N2-3; median ki67: 30% (82.7% &gt;10%). A 29% of patients showed sTIL=0%. Median sTIL infiltration was 5 (Q1-Q3 range [IQR], 0-10), with higher values in premenopausal (p&lt;0.001), grade 3 (p&lt;0.001), N+ (p&lt;0.001) and luminal B tumors (defined as PgR- and/or grade 3 and/or Ki67&gt;15%) (p&lt;0.001). Ki67 was significantly correlated with sTIL (ρ:0.39; p&lt;0.001). The percentage of sTIL was associated with pCR after nCT (OR: 1.045, 95%Ci 1.02-1.07, p=0.001). No prognostic impact of sTIL for OS or RFI was found in luminal A tumors. In luminal B cases (n=286), any grade of lymphocytic infiltration (defined as sTIL &gt; 0%) was associated with a shorter RFI both in univariate (p=0.01) and multivariate Cox models (HR: 4.83, 95%CI 1.28-18.21, p=0.02), with a non-significant trend for poorer OS (p=0.06). Conclusions: In luminal BC, an increased level of sTIL is associated with luminal B subtype characteristics such as higher proliferation, higher tumor grade and nodal involvement. Lymphocytic infiltration has been found to be a predictor of pCR after nCT, but, in contrast with hormone receptor-negative BC, it is also associated with a poorer prognosis for recurrence and a trend towards worse overall survival in luminal B tumors. [Table: see text]
Impact of neoadjuvant chemo-immunotherapy on surgical outcomes and time to radiation in triple negative breast cancer.
Authors: Sara P. Myers, Srinivasa Sevilimedu Veeravalli, V. Morgan Jones, Nour Abuhadra, Giacomo Montagna, George Plitas, Monica Morrow, Stephanie Downs-Canner
Journal: Journal of Clinical Oncology (2023)

555 Background: The impact of preoperative chemo-immunotherapy on surgical complications and timing of adjuvant therapy is not well understood. We examined the association between neoadjuvant pembrolizumab plus chemotherapy (NAC+P) compared to neoadjuvant chemotherapy alone (NAC) and treatment delays and postoperative complications in triple negative breast cancer (TNBC). The effect of immune-related adverse events (irAEs) on these outcomes was also compared. Methods: 143 women with stage II-III TNBC treated with NAC+P based on the KEYNOTE 522 (KN522) regimen from 8/2021-9/2022 were compared to 287 consecutive patients who received NAC prior to 7/2021. Baseline characteristics, time to treatments, and surgical complications were compared between KN522 and non-KN522, and among KN522 with/without irAEs using two-sample non-parametric tests. Linear regression evaluated association of irAEs with time to surgery and radiation. Conditional logistic regression identified factors associated with surgical complications among KN522 patients. Results: Age, BMI, race, ASA class, and mastectomy rates were similar among KN522 and non-KN522 patients. Interval from end of neoadjuvant treatment until surgery was one day longer for patients receiving NAC+P (median 32 days (IQR 27, 43) vs. 31 days (26, 37) non-KN522, p = 0.035). Time to radiation did not differ (p = 0.2). Postoperative complications occurred in 26 (9%) non-KN522 vs 12 (8.4%) of KN522 patients (p = 0.7) (Table). 55/144 (38%) of KN522 patients experienced 74 irAE; 42 (76%) required treatment. Pembrolizumab was held in 21 (38%) and discontinued permanently in 17 (31%). One KN522 patient experienced a fatal irAE (pneumonitis). Older age (coeff. 0.38, 95% CI 0.06-0.70, p = 0.02) and ASA class 4 (coeff. 53, 95% CI 14-92, p = 0.009) were associated with delays to surgery but irAE was not (p = 0.070). Neither presence of irAE (coeff. 6.8, 95% CI -0.74-14, p = 0.081) or number of irAEs (coeff. 4.1, 95% CI -1.2-9.3, p = 0.13) were associated with time to radiation. IrAEs were not associated with surgical complications (p = 0.5). Conclusions: Postoperative complications or delays to surgery or adjuvant radiation were similar in patients treated with NAC+P compared to NAC. IrAEs were not associated with delays to surgery or adjuvant radiation or postoperative complications. [Table: see text]
Sustained prognostic impact of primary tumor characteristics on long-term (overall) survival after distant metastasis in young ER+ HER2- breast cancer.
Authors: Janghee Lee, Eunhye Kang, Dong Seung Shin, Soong June Bae, Jun-Hee Lee, Jong-Ho Cheun, Han-Byoel Lee, Jai Min Ryu, Sung Gwe Ahn
Journal: Journal of Clinical Oncology (2023)

e13074 Background: Estrogen receptor (ER)+HER2- breast cancer has a good prognosis and is known to have more prolonged survival than other subtypes even after developing distant metastasis (DM). Predicting and improving long-term survival after DM is important, especially for young breast cancer patients with a long-life expectancy. This study aimed to analyze factors associated with long-term survival after DM in young ER+HER2- breast cancer (age ≤ 45). Methods: We retrospectively collected 2,951 young ER+HER2- breast cancer patients (age ≤ 45) who received primary surgery at three academic institutes between January 2000 and December 2011. Patients with survival data for at least 60 months after developing DM were analyzed. The patients must have received endocrine therapy for more than 24 months or until DM. Patients who had received neoadjuvant chemotherapy were excluded. Cox proportional hazard and binary logistic models were used to identify the factors related to post-metastatic overall survival (PMOS) and those associated with short- ( &lt; 60 months) versus long- (≥ 60 months) term survival after DM. Results: Of the 245 patients with DM, 188 had expired. The median follow-up was 117 (12–271) months from primary surgery and 38 (0–196) months from DM. In multivariate Cox analysis, lymph node (LN) metastasis of the primary tumor was identified as a risk factor of PMOS (hazard ratio [HR], 1.84; 95% confidence intervals [CI], 1.28–2.64; P = 0.001). LN metastasis of the primary tumor was a risk factor for short-term ( &lt; 60 months) survival (odds ratio [OR], 3.36; 95% CI, 1.66–6.79; P &lt; 0.001), and histologic grade (HG) I of the primary tumor was a favorable factor for long-term (≥ 60 months) survival (OR, 0.15; 95% CI, 0.03–0.76; P = 0.026) on multivariate analysis. In addition, early recurrence ( &lt; 60 months) (OR, 1.90; 95% CI, 1.04–3.47; P = 0.037), accompanying locoregional recurrence (LRR) (OR, 4.56; 95% CI, 1.96–10.59; P &lt; 0.001), and metastasis at multiple sites (OR, 2.90; 95% CI, 1.56–5.42); P &lt; 0.001) were negative indicators for long-term survival after DM. Conclusions: This study revealed that primary tumor characteristics such as LN metastasis and HG are sustained as prognostic factors for long-term survival after developing DM in young ER+HER2- breast cancer. Early recurrence ( &lt; 60 months), accompanying LRR, and metastasis at multiple sites were also poor prognostic factors.
Detection of homologous recombination deficiency (HRD) using a novel genomic and epigenomic liquid biopsy assay in patients with breast cancer.
Authors: Catalin Barbacioru, Jennifer Yen, Denis Tolkunov, Pegah Safabakhsh, Hao Wang, Andrew Gross, Brooke Overstreet, Colby Jenkins, Leylah Drusbosky, Lesli Ann Kiedrowski, Craig Eagle, Han-Yu Chuang
Journal: Journal of Clinical Oncology (2023)

556 Background: Homologous recombination and repair (HRR) deficiency (HRD) is characterized by genomic instability associated with dysfunction in BRCA1/2 or other HRR genes. Patients with breast cancer harboring an HRD phenotype with or without HRR mutations have derived clinical benefit from PARPi therapy. We have previously shown that GuardantINFINITY, a novel genomic and epigenomic liquid biopsy assay, can identify HRR SNVs, indels, rearrangements, copy number loss, reversions, and BRCA1 promoter methylation for patient selection and resistance monitoring, a major challenge for PARPi treatment. Here, we present a method of predicting HRD status by cfDNA using GuardantINFINITY in patients with advanced breast cancer. Methods: We developed a probabilistic genomic model to predict HRD status, inferred from genome-wide somatic SNV, indel, and CNV signatures indicative of BRCA1/2 deficiency, including large-scale state transitions (LST), whole-genome tumor loss of heterozygosity (LOH), telomeric allelic imbalance (TAI). A second probabilistic model, based on targeted measurements of genomic and epigenetic changes was learned from a subset of clinical samples to enhance the genomic model. The model was trained and tested on a cohort of over 12,000 GuardantOMNI and GuardantINFINITY clinical breast cancer samples to assess the sensitivity of accurately detecting deficiency in select HRR-genes ( BRCA1/2, PALB2, RAD51D). The aggregated predictive model was validated on an independent cohort of breast cancer samples. Results: The model based on genomic and epigenetic signals identified HRR-gene deficiency in a breast cancer cohort with a estimated 95% LoD of 22.5% tumor fraction and an AUC of 0.75 across all tumor fractions, an improvement in sensitivity over when only the genomic model is used (AUC of 0.7, 95% LoD of 28%). Specificity remained high for both models (100%, n = 83) in cancer free samples. Application of this model in a cohort of 1,101 patients with unselected breast cancer identified 390 patients with an HRD phenotype, of whom 192 patients had a known HRR-gene mutation. Of the 201 patients with a known pathogenic mutation in an HRR gene, 49 also had co-occurring LoH in the same gene, indicating biallelic loss. Conclusions: In this analysis, we demonstrate that a probabilistic model of genomic and methylation predictors can detect HRD status in patients with breast cancer from cfDNA using GuardantINFINITY. Additional analytical and clinical studies to further evaluate this model are ongoing. With HRD prediction, GuardantINFINITY provides a comprehensive minimally-invasive solution for PARPi and DNA damage treatment selection, longitudinal monitoring, and an exploratory platform for investigating epigenetic signals that may underpin resistance.